Drug Administration Research Articles

Development and validation of a high-performance liquid chromatography with tandem mass spectrometry method for quantification of tofacitinib in human plasma

Introduction. The use of tofacitinib as a pharmacological treatment for rheumatoid arthritis remains relevant in the light of the predicted increase in prevalence of the disease. At the same time, due to the withdrawal of several foreign pharmaceutical companies from the Russian pharmaceutical market, there has been a heightened demand for domestically produced medications, including generic formulations of tofacitinib. Registration of generic drugs necessitates the conduct of bioanalytical studies. Development and validation of a method for quantifying the analyte in biosamples remains to be a crucial part of the bioequivalence studies.Aim. The aim of this research is to develop and validate a method for the quantitative determination of tofacitinib in human plasma using high-performance liquid chromatography as the separation system coupled with a tandem mass spectrometer for detection purposes.Materials and methods. Biosample preparation was based on plasma proteins precipitation using acetonitrile. Baricitinib was selected as an internal standard. The analytical range of the method was 1.00 to 200.00 ng/mL and was further expanded to 0.30 to 200.00 ng/mL during the analytical phase of the study. The mobile phase consisted of water and acetonitrile, both acidified with formic acid (0.1 % v/v). The stationary phase was a Phenomenex Kinetex C18 column [100 × 3.0 mm, with a particle size of 5 µm (Phenomenex, USA)]. Sample separation and detection were carried out using high-performance liquid chromatography coupled with a tandem mass spectrometry (HPLC-MS/MS), operating in positive ion mode. The multiple reaction monitoring (MRM) transitions selected for the analyte and the internal standard were 313.30 to 173.00 m/z and 371.90 to 186.00 m/z, respectively.Results and discussion. The developed assay was validated in accordance with the current requirements of regulatory documentation from the EAEU (Eurasian Economic Union), FDA (US Food and Drug Administration), and EMA (European Medicines Agency) with the following parameters being evaluated: selectivity, specificity, carry-over, matrix effect, recovery, calibration curve, lower limit of quantitation, accuracy, precision, stability. The validated method was applied in the analytical part of a bioequivalence study of domestically produced generic tofacitinib.Conclusion. A method for the quantitative determination of tofacitinib in human blood plasma with an analytical range of 0.30–200.00 ng/mL was developed and validated. Application of the assay during the analytical phase of bioequivalence study of generic tofacitinib confirms the possibility of using the method in similar bioanalytical investigations.

Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n=34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.

The Advent of Molecular Targeted Therapies Against Cancer. Toward Multi‐Targeting Drugs Through Materials Engineering: A Possible Future Scenario

The authors, actively engaged in the development of mesoporous silica‐based solutions, initially for modified drug release, later for the smart administration of conventional chemotherapeutic cytotoxic drugs, present the evolution of the concept of targeted therapy across different disciplines. They also discuss the diverse therapeutic needs and related challenges (adverse drug effects) that have unfolded over the last 30 years. Nanomedicine potentialities, mainly against cancers, that have emerged globally during the intense research activity of the last few decades, are critically discussed. The authors glimpse the growing potential of immune‐based therapeutic solutions, including those assisted by nanotechnology, as well as molecular targeted therapies (MTT) on which they focus. The advantages offered by targeted molecular therapies, despite the limits of monotargeted therapies, suggest the engineering of multi‐targeted therapies. Nanomedicine solutions such as ligand‐specific internalization and pH‐sensitive drug release that they have extensively tested and recently presented in open literature, still remain available instruments. According to the authors, MTT can offer shining perspectives in the near future that will depend on a thorough comprehension of nanostructures synthesis and tumor physiology. This article gives an interdisciplinary point of view tailored for non‐specialist readers imagining possible future scenarios in the field.

Smart responsive in situ hydrogel systems applied in bone tissue engineering

The repair of irregular bone tissue suffers severe clinical problems due to the scarcity of an appropriate therapeutic carrier that can match dynamic and complex bone damage. Fortunately, stimuli-responsive in situ hydrogel systems that are triggered by a special microenvironment could be an ideal method of regenerating bone tissue because of the injectability, in situ gelatin, and spatiotemporally tunable drug release. Herein, we introduce the two main stimulus-response approaches, exogenous and endogenous, to forming in situ hydrogels in bone tissue engineering. First, we summarize specific and distinct responses to an extensive range of external stimuli (e.g., ultraviolet, near-infrared, ultrasound, etc.) to form in situ hydrogels created from biocompatible materials modified by various functional groups or hybrid functional nanoparticles. Furthermore, “smart” hydrogels, which respond to endogenous physiological or environmental stimuli (e.g., temperature, pH, enzyme, etc.), can achieve in situ gelation by one injection in vivo without additional intervention. Moreover, the mild chemistry response-mediated in situ hydrogel systems also offer fascinating prospects in bone tissue engineering, such as a Diels–Alder, Michael addition, thiol-Michael addition, and Schiff reactions, etc. The recent developments and challenges of various smart in situ hydrogels and their application to drug administration and bone tissue engineering are discussed in this review. It is anticipated that advanced strategies and innovative ideas of in situ hydrogels will be exploited in the clinical field and increase the quality of life for patients with bone damage.

Guaifenesin: The Ubiquitous Orphan.

Guaifenesin, a widely used ingredient in over-the-counter cough and cold medications, has been a subject of debate regarding its efficacy in treating respiratory conditions. Despite its historical use and US Food and Drug Administration approval, recent studies have questioned its claimed expectorant effect and its effectiveness in managing symptoms. This article examines the available evidence, highlighting the lack of significant benefits over placebo for upper respiratory disease. The rationale for clinical use is examined alongside the potential downside and alternatives to recommending guaifenesin as a treatment option.

Pattern and predictor of hookworm re-infection among schoolchildren in three districts of Amhara Region, northwest Ethiopia.

Despite integrated prevention and control measures, the prevalence of hookworm is still high in Ethiopia. The re-infection rates and predictors are poorly addressed. Therefore, this study aimed to determine the patterns of hookworm re-infection rates and predictors among schoolchildren in northwest Ethiopia. A prospective follow-up study was conducted among 86 schoolchildren from May to December 2022. Data on predictors was collected using a questionnaire. Stool samples were collected and processed via Kato-Katz, McMaster, and spontaneous tube sedimentation techniques. All hookworm-infected children were treated with albendazole and followed for six months. The re-infection rates of hookworm were checked in the 4th and 6th months. Data was entered into Epi-data version 3.1 and analysed using SPSS version 25. Descriptive statistics were used to compute the re-infection rate. The associations of predictors with hookworm re-infection rates were calculated by logistic regression. Variables with a p-value < 0.05 were considered statistically significant. Of the 86, 81 schoolchildren completed the study. The prevalence of hookworm re-infection in the 4th and 6th months was 23.5% and 33.3%, respectively. Living with family members greater than five (p = .017), poor utilization of latrine (p = .008), infrequent shoe wear (p = .039), and participating in irrigation (p = .020) were the predictors significantly associated with hookworm re-infections. The re-infection rate was high during the fourth and sixth months. Participating in irrigation, infrequent shoe wear, and poor latrine utilization were predictors of hookworm re-infection. Therefore, mass drug administration, regular shoe wearing, and health education should be advocated.

Safety assessment of tranexamic acid: real-world adverse event analysis from the FAERS database

BackgroundIn recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its powerful efficacy, concerns regarding its adverse reactions persist, necessitating comprehensive safety assessment. This study analyzed real-world data from the U.S. Food and Drug Administration to investigate TXA-related adverse events, aiming to elucidate its safety and optimize patient treatment.MethodsThe adverse drug event data concerning TXA from 2004 Q1 to 2023 Q3 were collected. Following data standardization, a variety of signal quantification techniques, including the reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and empirical Bayes geometric mean were used for analysis.ResultsAfter analyzing 16,692,026 adverse event reports, a total of 1,574 cases of adverse events related to TXA were identified, spanning 23 system organ classes and 307 preferred terms. In addition to the common thrombosis-related Vascular disorders (n = 386) and Cardiac disorders (n = 377), adverse reactions in the Nervous system disorders category were also observed (n = 785), including Myoclonus (n = 70), Status epilepticus (n = 43), and Myoclonic epilepsy (n = 17). Furthermore, this study uncovered adverse effects such as Renal cortical necrosis, Hepatic cyst rupture, and Vascular stent stenosis, which were not previously mentioned in the instructions. Although these occurred infrequently, they exhibited high signal strength. Both Retinal artery occlusion and Vascular stent thrombosis disorder were frequent and exhibited high signal strength as well. It is worth noting that 78 cases of adverse reactions were caused by confusion between incorrect product administration.ConclusionOur research suggests that TXA has some adverse reactions that are being overlooked. As a cornerstone medication in hemorrhage treatment, it’s crucial to monitor, identify, and address these adverse reactions effectively.

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis and immunomodulation. Moreover, the recent U.S. Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represent a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications. This article is protected by copyright. All rights reserved.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system

Evaluating the sources and types of dietary and nutritional advice for patients with alopecia areata.

Although there are now two Food and Drug Administration (FDA)-approved treatments for severe alopecia areata (AA), many patients still resort to non-medical therapies and lifestyle modifications such as diet and nutrition. The goal of this study was to evaluate the sources and types of dietary and nutritional advice for patients with AA. We distributed a cross-sectional national survey using the National Alopecia Areata Foundation's email list-serv between August 2022 and January 2023. Most respondents were White (76.3%), employed (58.3%) females (84.4%) with a mean age of 52 years. 163 (19.1%) respondents reported receiving diet and/or nutritional advice and 418 (49.5%) respondents reported searching for diet and/or nutritional advice to help with their AA; the most common source of advice was online. The most common dietary changes were the use of vitamins or supplements (30.6%), adherence to diets (23.2%), and the addition of specific foods (21.4%). 209 (50.2%) respondents reported no change in their disease and 197 (47.4%) respondents reported no change in how they felt about their disease compared to before they tried the change. Many AA patients search for or receive unsolicited dietary and nutritional advice and subsequently modify their behavior to manage their disease. However, the efficacy of these changes is unclear. Providers should be mindful of the sources through which patients obtain treatment information as well as the lifestyle changes patients make to counsel patients with evidence-based information. Further investigation is needed to better characterize the direct and indirect costs of dietary and nutritional modification in the treatment of AA.

Advances of monoclonal antibodies and analysis of marketed antibody drugs

In recent years, there has been a frequent occurrence of various epidemics worldwide such as COVID-19, monkeypox, influenza, and others additionally, there has been an increase in the number of new patients diagnosed with various types of tumors. Traditional drugs have limited effectiveness against emerging infectious diseases, tumors, and autoimmune diseases. However, with the emergence of hybridoma technology, monoclonal antibodies have achieved extensive applications and antibody drugs are playing an important role in modern medicine. Monoclonal antibodies have undergone various development stages, starting from mouse-derived antibodies to human-mouse chimeric antibodies, humanized antibodies, and ultimately human antibodies. Throughout this process, their immunogenicity has gradually decreased, while their safety for human use steadily increased. Fully human antibodies are currently the safest form of antibody, because their sequences all come from human sources and they do not induce human anti-murine antibody reactions. With the advance of genetic engineering technology, flow cytometry coupled to single B cell gene amplification technology has made it easier to construct and screen for fully human monoclonal antibodies. The development of antibody drugs has provided new opportunities, and the market for monoclonal antibody drugs will further expand. This article reviews the research progress of monoclonal antibodies and presents information on the 163 monoclonal antibody drugs approved by the United States Food and Drug Administration (FDA) as of Oct 1st, 2023. The aim is to offer new insights for the development and production of monoclonal antibodies in China.

A retrospective analysis of drugs associated with the development of cutaneous squamous cell carcinoma reported by patients on the FDA’s adverse events reporting system

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer arising from squamous cells of the epidermis. Most cases of cSCC have a good prognosis if detected and treated early; however, certain cases can be aggressive. The primary risk factor for cSCC is prolonged ultraviolet radiation from sun exposure, leading to DNA mutations. Other risk factors have also been observed, including adverse reactions to medications, particularly immunosuppressants. A query of the Food and Drug Administration Adverse Events Reporting System (FAERS) was done, and all reported events of cSCC as adverse events to medication were recorded along with demographic data of patients affected. A total of 4,792 cases of cSCC as an adverse event to medication were reported between 1997 and 2023. Lenalidomide, a chemotherapeutic drug, had the most cases of cSCC as an adverse event. Nine of the top 10 drugs associated with cSCC had immunosuppressive characteristics. While males had higher odds of cSCC associated with corticosteroids and calcineurin inhibitors, females had higher odds of cSCC related to monoclonal antibodies. Geriatric patients accounted for the majority of cSCC cases at 59.7%. Drawing on data from the FAERS database, there’s been a consistent increase in cSCC cases as a side-effect to certain medications, with most having immunosuppressive characteristics. Since there is a lack of up-to-date literature overviewing the most implicated medications for cSCC, we aimed to illustrate this better, as well as patient demographics, to better guide clinicians when prescribing these medications.

Evaluating the accuracy of Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) responses to United States Food and Drug Administration (FDA) frequently asked questions about dental amalgam

BackgroundThe use of artificial intelligence in the field of health sciences is becoming widespread. It is known that patients benefit from artificial intelligence applications on various health issues, especially after the pandemic period. One of the most important issues in this regard is the accuracy of the information provided by artificial intelligence applications.ObjectiveThe purpose of this study was to the frequently asked questions about dental amalgam, as determined by the United States Food and Drug Administration (FDA), which is one of these information resources, to Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) and to compare the content of the answers given by the application with the answers of the FDA.MethodsThe questions were directed to ChatGPT-4 on May 8th and May 16th, 2023, and the responses were recorded and compared at the word and meaning levels using ChatGPT. The answers from the FDA webpage were also recorded. The responses were compared for content similarity in “Main Idea”, “Quality Analysis”, “Common Ideas”, and “Inconsistent Ideas” between ChatGPT-4’s responses and FDA’s responses.ResultsChatGPT-4 provided similar responses at one-week intervals. In comparison with FDA guidance, it provided answers with similar information content to frequently asked questions. However, although there were some similarities in the general aspects of the recommendation regarding amalgam removal in the question, the two texts are not the same, and they offered different perspectives on the replacement of fillings.ConclusionsThe findings of this study indicate that ChatGPT-4, an artificial intelligence based application, encompasses current and accurate information regarding dental amalgam and its removal, providing it to individuals seeking access to such information. Nevertheless, we believe that numerous studies are required to assess the validity and reliability of ChatGPT-4 across diverse subjects.

A review of the toxicity of ingredients in e-cigarettes, including those ingredients having the FDA's "Generally Recognized as Safe (GRAS)" regulatory status for use in food.

Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.

Comparison of QT interval readings between smartwatch ECG combined with artificial intelligence and 12-lead ECG in subjects hospitalized for antiarrhythmic drug initiation and follow-up

Abstract Background/Introduction Class III antiarrhythmic drugs (AADs) are effective for the maintenance of sinus rhythm (SR) in subjects with atrial fibrillation (AF). However, several require initial hospitalization for QT interval monitoring using the 12-lead ECG. Purpose The purpose of this study was to evaluate the feasibility of using a smartwatch single lead ECG combined with a deep learning algorithm for routine QT interval determination in the context of AAD initiation. Methods A deep learning model was developed using smartwatch and Holter ECG recordings to estimate corrected QT intervals. To evaluate the performance of this model, we carried out a prospective study on subjects hospitalized for initiation of sotalol and/or dofetilide. Subjects recorded near simultaneous (maximal 2 minutes apart) smartwatch ECGs (Apple Watch Series 6) and 12-lead ECG (Mac 5500 HD ECG or GE Carescape B450) right before and 2-3 hours after drug administration twice a day for 2-3 days. Blinded double annotation followed by adjudication of disagreement provided a reference heart rhythm (NSR or AF) and QTc interval. The tangent method was used for QTc interval determination. Bland-Altman analysis was performed to assess the agreement between QTc measures. Results Fifty subjects (mean age 67.4±10.9 years, 64% male) were enrolled in the study from February 2022 to October 2022. Out of 386 monitoring visits, 321 near simultaneous pairs of ECGs were collected with a mean delay of +15.0±41.1s for the smartwatch ECG compared to the 12-lead ECG. Overall, a mean QTcF reference value of 419.9±34.0 ms was observed (435.2±38.4 ms for QTcB, r=0.83 between annotators[BL2] ). Among the 139 pairs with 12-lead ECG found in NSR, we observed a mean QTcF difference of +19.7 ms and limits of agreements equal to -21.5 ms and 60.8 ms, with AI-facilitated measurement. In comparison, a mean QTcF difference of +22.5 ms and limits of agreements equal to -23.8 ms and 68.8 ms were observed for manual readings of smartwatch ECGs instead. Conclusion(s): Our findings suggest that a smartwatch ECG deep learning approach can estimate the QT interval with a fair agreement compared to standard 12-lead monitoring during AAD initiation. This measurement method appears to be at least as accurate as manual measurements on smartwatch ECGs. With further validation, the smartwatch-based automatic detection of QT interval prolongation, could be used for a faster, safe, and extended outpatient QT interval monitoring.Bland-Altman plots

Insight into the Functional Dynamics and Challenges of Exosomes in Pharmaceutical Innovation and Precision Medicine

Of all the numerous nanosized extracellular vesicles released by a cell, the endosomal-originated exosomes are increasingly recognized as potential therapeutics, owing to their inherent stability, low immunogenicity, and targeted delivery capabilities. This review critically evaluates the transformative potential of exosome-based modalities across pharmaceutical and precision medicine landscapes. Because of their precise targeted biomolecular cargo delivery, exosomes are posited as ideal candidates in drug delivery, enhancing regenerative medicine strategies, and advancing diagnostic technologies. Despite the significant market growth projections of exosome therapy, its utilization is encumbered by substantial scientific and regulatory challenges. These include the lack of universally accepted protocols for exosome isolation and the complexities associated with navigating the regulatory environment, particularly the guidelines set forth by the U.S. Food and Drug Administration (FDA). This review presents a comprehensive overview of current research trajectories aimed at addressing these impediments and discusses prospective advancements that could substantiate the clinical translation of exosomal therapies. By providing a comprehensive analysis of both the capabilities and hurdles inherent to exosome therapeutic applications, this article aims to inform and direct future research paradigms, thereby fostering the integration of exosomal systems into mainstream clinical practice.

P.024 Sex and gender reporting in clinical trials among neurological US Food and Drug Administration approvals

Background: Sex and gender are related but distinct determinants of disease, treatment response, and research reproducibility whose consideration is increasingly required for research funding. Nevertheless, the quality of sex and gender reporting in neurological randomized controlled trials (RCTs) remains unknown. Methods: This ongoing study of RCTs associated with Food and Drug Administration neurological drug approvals aims to determine the frequency of accurate reporting of RCT participants’ sex and gender. Secondary outcomes include changes in reporting over time and RCT design characteristics. Results: Preliminary analysis included 145 RCTs (153,410 participants) associated with 77 medications approved in 1985-2023, most commonly for epilepsy (19%), migraine (16%), and multiple sclerosis (16%). Sixty-six RCTs (45.5%) used sex-related terms appropriately. Nine RCTs (6.2%) reported gender accurately. Fifty-three RCTs (37%) used sex- or gender-related terms interchangeably. There are no statistically significant differences in the proportions of studies reporting sex and/or gender accurately when comparing those published until versus after 2017. No RCT reported sex or gender collection methods, definitions of sex or gender, or including sex or gender minority participants. Conclusions: Preliminary results suggest shortcomings in reporting sex and, especially, gender accurately and inclusively among neurological drug RCTs and no significant improvement thereof in recent years.

Prophylactic administration of glycopyrrolate prevents vasovagal responses induced by pulsed field ablation in patients with atrial fibrillation

Abstract Background The FarapulseTM system was the first pulsed field ablation device to receive regulatory approval. Vagal Responses (VR) during pulmonary vein isolation (PVI) with this pentaspline device are frequent and often require back-up pacing or the administration of parasympathetic drugs. Glycopirrolate (GLY) is a medication of the muscarinic anticholinergic group; its efficacy for VR prevention when administered prophylactically before PVI has never been reported. Objective To evaluate the effectiveness of prophylactic intravenous administration of GLY on VRs induced by PFA. Methods Consecutive AF patients undergoing first-time PVI with PFA via the FarapulseTM system between April and October 2023 were prospectively enrolled in 3 European centers. Prophylactic administration of GLY (0.2 mg intravenous administration before femoral vein puncture) [Group GLY(+)] was adopted based on operator’s preference. VR was defined as at least one of the following: sinus bradycardia (&amp;lt;40 beats/min), asystole (&amp;gt;6 sec), or atrioventricular block (AVB) occurring immediately after a pulsed electric field application. VRs and maximum pause duration (maximum RR interval) were determined for each PV. Temporary backup pacing was performed as per the operator's preference. Results We enrolled 141 patients [GLY(+): 64 patients; GLY(-): 77 patients] undergoing PVI with the pentaspline FarapulseTM system. Median age was 54.1 years (54.1- 70), and 76 (54%) patients were males with an average CHA2DS2-VASc Score of 1.0 (0 – 2). A total of 563 PVs, including 3 left common PVs and 2 accessory middle PVs, were successfully isolated with the FarapulseTM PFA system. There were no statistically significant differences in baseline and procedural characteristics between two groups. VRs during PVI occurred in a total of 53 (37.6%) patients. GLY administration reduced significantly the incidence of any VRs (4.7% vs 64.9%; p&amp;lt;0.001) (Figure 1A). Additionally, GLY resulted in a lower incidence of VRs during LSPV (4.7% vs 62.3%; p&amp;lt;0.001) and LIPV (1.6% vs 9.1%; p&amp;lt;0.001) (Figure 1B) isolation and the need for temporary backup pacing during LSPV (24.7% vs 1.6%; p&amp;lt;0.001) isolation. Maximum pause duration was significantly shorter in the GLY(+) group after PFA of LSPV (1195 vs 3459 sec; p&amp;lt;0.001), LIPV (1128 vs 1556 sec; p&amp;lt;0.001), RSPV (1138 vs 1607 sec; p&amp;lt;0.001) and RIPV (1103 vs 1343 sec; p&amp;lt;0.001) compared to GLY(-) group (Figure 1C). Conclusions Glycopyrrolate is highly effective in the prevention of VRs induced by PFA ablation in AF patients undergoing first-time PVI.Figure 1

Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report

BackgroundPrevious reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam.Case presentationA 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups.ConclusionRemimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia.